Modulation of the adaptive immune compartment by stromal fibroblasts

This project will focus on better understanding the interactions between stromal fibroblasts and the adaptive immune system and will utilise model systems to investigate how fibroblasts with pro or anti-inflammatory phenotypes differentially regulate immune responses to breast tumours grown in immune competent mice. Clinically, breast cancers are largely refractory to inhibitors of immune checkpoint molecules such as CTLA-4 and PD-1 antibodies, suggesting that the stromal microenvironment is highly immune suppressive. A likely reason for this is that although infiltration of cytotoxic CD8+ T cells is a good prognostic indicator in breast cancers, a large proportion of tumours show poor T cell recruitment or polarisation of the T cells towards a type II tumour supportive phenotype. There is increasing evidence that cancer-associated fibroblasts (CAFs) play a key role in these processes. First, a significant proportion of breast tumours have a high fibroblast content and associated deposition of extracellular matrix components that can create a barrier for leucocyte infiltration. Second, work in both the Isacke laboratory at the Institute of Cancer Research (ICR) and at MedImmune support a direct immunomodulatory role for CAFs. In particular the Isacke laboratory has strong preliminary data demonstrating (a) that CAFs directly isolated from non-aggressive, but not related aggressive, mouse tumours have a gene expression signature associated with activation of the adaptive immune system, and (b) that this correlates with the non-aggressive tumours i) having a higher CD8+/CD4+ T cell ratio, ii) showing polarisation of the infiltrating T cells towards a type 1 anti-tumour phenotype, and iii) unlike the aggressive tumours, growing much more rapidly in immunocompromised mice in the absence of an intact immune system compared to syngeneic Balb/c mice.

Using the resources available at MedImmune (e.g. additional immunocompetent mouse models, high level immunology and bioinformatics expertise, novel antibodies developed to various immune modulatory proteins), this BBSRC CASE studentship will build on this preliminary data and by working across both sites will

fully characterise models of CAF-mediated immune suppression/activation

using these models, determine the gene expression changes associated with different CAF populations altered in their ability to modulate the adaptive immune compartment and build a signature of differentially regulated genes expressed in CAFs with immune-suppressive vs. immune-stimulatory phenotypes

identify key components mediating CAF-adaptive immune cell interactions and explore using bioinformatics the relevance of these in other disease contexts e.g. wound healing, inflammatory disorders

identify how these components interact with other key immune signalling pathways using antibodies to stimulate/inhibit these pathways in the different preclinical models

The objectives of this project will be to determine (a) the mechanism by which stromal fibroblasts modulate the balance of suppression and promotion of adaptive immunity in disease, and (b) how these CAF-mediated effects interact with other known immunomodulatory pathways, for example immune checkpoint blockade using PD-1/PD-L1 antibodies.